Sleep fragmentation (SF, sleep interrupted by repeated arousals/awakenings) and chronic intermittent hypoxia (CIH) are the two primary events associated with obstructive sleep apnea (OSA). In the last four years of this project, we demonstrated that CIH enhances both respiratory long-term facilitation (LTF, a persistent increase in respiratory activity after episodic hypoxia) and hypoxic phrenic response in rats, and the CIH-induced enhancement requires serotonergic mechanisms. In contrast to CIH, SF, characterized by a significant loss of deep sleep but not total sleep time, has been much less studied, particularly with respect to respiratory control. Our preliminary data suggest that SF, achieved by periodic, forced locomotion in a rotating drum, eliminates LTF, counteracts the CIH effect on LTF and impairs chemo-reflexes to hypoxia and hypercapnia, and that the SF-induced impairments require adenosinergic mechanisms. Our working model is that SF increases extracellular adenosine levels (may also up-regulate adenosine A1 receptors) near respiratory motoneurons, which reduces glutamate and serotonin release from nerve terminals via A1 receptor-mediated pre-synaptic inhibition, thus impairing chemo-reflexes and LTF, respectively.
Three specific aims are proposed.
Aim 1 will test the hypothesis that SF eliminates ventilatory, hypoglossal and phrenic LTF, and impairs ventilatory chemo-reflexes.
Aim 2 will test the hypothesis that SF impairs the CIH effect on LTF.
Aim 3 will investigate the role of A1 receptors in the SF-induced impairments by testing the hypotheses that: 1) the SF-impaired LTF and chemo-reflexes are restored by the A1 receptor antagonist 8-CPT (8-cyclo-pentyl-theophylline, i.p.);2) the impaired phrenic LTF is also restored by microinjection of 8-CPT into the phrenic motor nucleus region (PMN);3) phrenic LTF is abolished by microinjecting A1 receptor agonist into PMN;4) SF increases adenosine levels near respiratory motoneurons;and 5) SF inhibits the episodic hypoxia-induced serotonin release in PMN, which is restored by A1 receptor antagonism. The information derived from the proposed studies will contribute to our understanding of the neural plasticity in respiratory motor control and provide evidence in favor of the notion that SF may exacerbate OSA via certain impaired ventilatory control mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064912-09
Application #
7643358
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Twery, Michael
Project Start
2000-07-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
9
Fiscal Year
2009
Total Cost
$408,599
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Cao, Ying; McGuire, Michelle; Liu, Chun et al. (2012) Phasic respiratory modulation of pharyngeal collapsibility via neuromuscular mechanisms in rats. J Appl Physiol 112:695-703
Liu, Chun; Cao, Ying; Malhotra, Atul et al. (2011) Sleep fragmentation attenuates the hypercapnic (but not hypoxic) ventilatory responses via adenosine A1 receptors in awake rats. Respir Physiol Neurobiol 175:29-36
Cao, Ying; Ling, Liming (2010) Urethane inhibits genioglossal long-term facilitation in un-paralyzed anesthetized rats. Neurosci Lett 477:124-8
Cao, Ying; Liu, Chun; Ling, Liming (2010) Glossopharyngeal long-term facilitation requires serotonin 5-HT2 and NMDA receptors in rats. Respir Physiol Neurobiol 170:164-72
McGuire, Michelle; Liu, Chun; Cao, Ying et al. (2008) Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats. J Appl Physiol 105:942-50
Ling, Liming (2008) Serotonin and NMDA receptors in respiratory long-term facilitation. Respir Physiol Neurobiol 164:233-41
McGuire, Michelle; Tartar, Jaime L; Cao, Ying et al. (2008) Sleep fragmentation impairs ventilatory long-term facilitation via adenosine A1 receptors. J Physiol 586:5215-29
McGuire, Michelle; Ling, Liming (2005) Ventilatory long-term facilitation is greater in 1- vs. 2-mo-old awake rats. J Appl Physiol 98:1195-201
McGuire, Michelle; Zhang, Yi; White, David P et al. (2005) Phrenic long-term facilitation requires NMDA receptors in the phrenic motonucleus in rats. J Physiol 567:599-611
McGuire, Michelle; Zhang, Yi; White, David P et al. (2004) Serotonin receptor subtypes required for ventilatory long-term facilitation and its enhancement after chronic intermittent hypoxia in awake rats. Am J Physiol Regul Integr Comp Physiol 286:R334-41

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